The combinatorial library of novel potential anticancer agents, namely, 2-(alkyl-, alkaryl-, aryl-, hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines, was synthesized by the heterocyclization of the alkyl-, alkaryl-, aryl-, hetarylcarboxylic acid (3H-quinazoline-4-ylidene)hydrazides by oxidative heterocyclization of the 4-(arylidenehydrazino)quinazolines using bromine, and by the heterocyclization of N-(2-cyanophenyl)formimidic acid ethyl ester. The optimal method for synthesis of the s-triazolo[1,5-c]quinazolines appeared to be cyclocondensation of the corresponding carboxylic acid (3H-quinazoline-4-ylidene)hydrazides. The compounds’ structures were established by 1H, 13C NMR, LC- and EI-MS analysis. The in vitro screening of anticancer activity determined the most active compound to be 3,4,5-trimethoxy-N′-[quinazolin-4(3H)-ylidene]benzohydrazide (3.20) in micromolar concentrations with the GI50 level (MG_MID, GI50 is 2.29). Thus, the cancer cell lines whose growth is greatly inhibited by compound 3.20 are: non-small cell lung cancer (NCI-H522, GI50=0.34), CNS (SF-295, GI50=0.95), ovarian (OVCAR-3, GI50=0.33), prostate (PC-3, GI50=0.56), and breast cancer (MCF7, GI50=0.52), leukemia (K-562, GI50=0.41; SR, GI50=0.29), and melanoma (MDA-MB-435, GI50=0.31; SK-MEL-5, GI50=0.74; UACC-62, GI50=0.32). SAR-analysis is also discussed.

In the continuing search for novel, biologically effective heterocyclic agents, several methods for the synthesis of 2‐heteroaryl‐[1,2,4]triazolo[1,5‐c]quinazoline‐5(6 H)‐thiones have been developed: thiolation of oxo derivatives, [5+1] cyclocondensation of [2‐(3‐heteroaryl‐[1,2,4]triazol‐5‐yl)phenyl]amines with carbon disulfide, potassium ethyl xanthogenate, or aryl isothiocyanates, and in situ reaction of 2‐isothiocyanatobenzonitrile with hydrazides. A series of N‐R‐2‐[(2‐heteroaryl‐[1,2,4]triazole‐[1,5‐c]quinazoline‐5‐yl)thio]acetamides were obtained by aminolysis of the corresponding acetic acids and alkylation of potassium thiolates with N‐R‐2‐chloroacetamides. It was established that some potassium thiolates, 4 a–4 d, 4 h, and 4 i, had high antibacterial activity against Staphylococcus aureus with a minimum inhibitory concentration of 12.5 μg mL−1 and minimum bactericidal concentration of 25 μg mL−1, which exceeded the values for trimethoprim. In addition, {2‐[3‐(1 H‐indole‐2‐yl)‐1 H‐1,2,4‐triazol‐5‐yl]phenyl}amine 2 i was investigated in the concentration range 100–0.01 μM at 59 lines of nine cancer cell types, and showed a mean effective concentration at 3.12–7.03 μM and cytotoxic effect at 15.56–67.38 μM. The possible mechanisms of activity were predicted by molecular docking studies to S. aureus dihydrofolate reductase and epidermal growth factor receptor kinase.

Several novel 6-thio-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-based compounds containing an ω-(dialkylamino(heterocyclyl)]alkyl fragment were synthesized to examine their anticancer activity. Some of the 6-{[ω-(hetero-cyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (3.1–3.10) were obtained by the nucleophilic substitution of 6-[ω-halogenalkyl]thio-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (2.1–2.8) with azaheterocycles. Alternatively, compounds 3.1–3.22 were synthesized by alkylation of 3-R-6-thio-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts (1.1–1.4) with (2-chloroethyl)-N,N-dialkylamine hydrochlorides or 1-(2-chloroethyl)heterocycle hydrochlorides. The structures of compounds were elucidated by 1H, 13C NMR, LC–MS and EI-MS analysis. Then anticancer and antibacterial, bioluminescence inhibition of Photobacterium leiognathi Sh1 activities of the substances were tested in vitro. It was found that compound 3.18 possessed a wide range of anticancer activity against 27 cell lines of cancer: non-small cell lung, colon, CNS, ovarian, renal, prostate, breast, melanoma and leukemia (log GI50 < −5.65). The “structure-activity” relationship was discussed. COMPARE analysis for synthesized anticancer active compounds was performed.

Nine novel acyl thioureas were synthesized. Their identities and purities were confirmed by LC-MS spectra; each structure was elucidated by elemental analysis, IR, 1 Н and 13 C NMR spectra. Applying an in vitro screening of their antifungal potential, three substances (3, 5, and 6) could be selected as showing high activity against 11 fungi and 3 Phytophthora strains of phytopathogenic significance. Analysis of gene toxicity with the Salmonella reverse mutagenicity test, as an assessment of drug likeness, lipophilicity, and calculations of frontier molecular orbitals assign a low toxicity profile to these compounds. Molecular docking studies point to 14α-demethylase (CYP51) and N-myristoyltransferase (NMT) as possible fungal targets for growth inhibition. The findings are discussed with respect to structure-activity relationship (SAR).

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